This invention relates to 11xcex2-halogen-7xcex1-substituted estratrienes of general formula I 
in which
R3 means a hydrogen atom, a hydrocarbon radical with up to 8 carbon atoms or a radical of partial formula R3xe2x80x2xe2x80x94C(O)xe2x80x94, in which R3xe2x80x2 means a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms or a phenyl radical,
R7 means a radical of formula xe2x80x94Axe2x80x94Bxe2x80x94Zxe2x80x94R20,
xe2x80x83in which
A stands for a direct bond or a benzylidene radical, whereby the methylene group is bonded to the 7-carbon atom of the steroid, or a phenylene radical,
B stands for a straight-chain or branched-chain alkylene, alkenylene or alkinylene group with 3 to 14 carbon atoms, and
Z stands for xe2x80x94NR21xe2x80x94 and R21 stands for a C1-C3 alkyl group,
xe2x80x83whereby then R20 means
a hydrogen atom,
a straight-chain or branched-chain alkyl,
alkenyl or alkinyl group with up to 10 carbon atoms or one of groupings
xe2x80x94Dxe2x80x94CnF2n+1, whereby D is a straight-chain or branched-chain alkylene, alkenylene or alkinylene group with up to 8 carbon atoms and n is an integer from 1 to 8,
xe2x80x94Lxe2x80x94CHxe2x95x90CFxe2x80x94CpF2p+1, whereby L is a straight-chain or branched-chain alkylene, alkenylene or alkinylene group with 2 to 7 carbon atoms and p is an integer from 2 to 7,
xe2x80x94Dxe2x80x94Oxe2x80x94(CH2)q-aryl, whereby D has the already indicated meaning, q is 0, 1, 2 or 3, and aryl stands for a phenyl radical, 1- or 2-naphthyl radical or a heteroaryl radical that is optionally substituted in one or two places,
xe2x80x94Dxe2x80x94Oxe2x80x94(CH2)rxe2x80x94CnF2n+1, whereby D and n have the already indicated meanings and r stands for an integer from 1 to 5, or
R20 and R21 with the nitrogen atom to which they are bonded form a saturated or unsaturated heterocycle with 5 or 6 chain links, which optionally contains one or two additional heteroatoms, selected from nitrogen, oxygen and sulfur, and optionally is substituted, or
Z stands for xe2x80x94SOx and x stands for 0, 1 or 2,
xe2x80x83whereby R20 then means
a straight-chain or branched-chain alkyl, alkenyl or alkinyl group with up to 10 carbon atoms, or one of groupings
xe2x80x94Dxe2x80x94C F2n+1, whereby D is a straight-chain or branched-chain alkylene, alkenylene or alkinylene group with up to 8 carbon atoms and n is an integer from 1 to 8,
xe2x80x94Lxe2x80x94CHxe2x95x90CFxe2x80x94CpF2p+1, whereby L is a straight-chain or branched-chain alkylene, alkenylene or alkinylene group with 2 to 7 carbon atoms and p is an integer from 2 to 7,
xe2x80x94Dxe2x80x94Oxe2x80x94(CH2)q-aryl, whereby D has the already indicated meaning, q is 0, 1, 2 or 3, and aryl stands for a phenyl radical, 1- or 2-naphthyl radical or a heteroaryl radical that is optionally substituted in one or two places,
xe2x80x94Dxe2x80x94Oxe2x80x94(CH2)rxe2x80x94CnF2n+1, whereby D and n have the already indicated meanings and r stands for an integer from 1 to 5, or
Z stands for xe2x80x94NR31,
xe2x80x83whereby then R20 is a straight-chain or branched-chain, optionally partially fluorinated alkyl, alkenyl or alkinyl radical with up to 14 carbon atoms, which can be interrupted by one to three heteroatoms xe2x80x94Oxe2x80x94 and xe2x80x94Sxe2x80x94 and groupings xe2x80x94NR32xe2x80x94, in which R32 is a hydrogen atom or a C1-C3 alkyl radical, an aryl or heteroaryl radical that is optionally substituted in one or two places, a C3-C10 cycloalkyl radical that is optionally substituted in one or two places, a C4-C15 cycloalkylalkyl radical that is optionally substituted in one or two places, a C7-C20 aralkyl radical that is optionally substituted in one or two places, a heteroaryl-C1-C6 alkyl radical that is optionally substituted in one or two places or an optionally substituted aminoalkyl radical, and R31 is a radical of formula xe2x80x94C(O)R33 or xe2x80x94CH2xe2x80x94R33, whereby then R33 is a straight-chain or branched-chain, optionally partially fluorinated alkyl, alkenyl or alkinyl radical with up to 14 carbon atoms, which can be interrupted by one to three heteroatoms xe2x80x94Oxe2x80x94 and xe2x80x94Sxe2x80x94 and groupings xe2x80x94NR32xe2x80x94, in which R32 is a hydrogen atom or a C1-C3 alkyl radical, an aryl or heteroaryl radical that is optionally substituted in one or two places, a C3-C10 cycloalkyl radical that is optionally substituted in one or two places, a C4-C15 cycloalkylalkyl radical that is optionally substituted in one or two places, a C7-C20 aralkyl radical that is optionally substituted in one or two places, a heteroaryl-C1-C6 alkyl radical that is optionally substituted in one or two places, an optionally substituted aminoalkyl radical or a biphenylene radical,
xe2x80x83whereby side chain R7 cannot have the meanings that are indicated there in PCT/EP97/04517 for SK,
R11 means a fluorine or chlorine atom,
R17 means a hydrogen atom or a radical of partial formula R17xe2x80x2xe2x80x94C(O)xe2x80x94, in which R17xe2x80x2 is a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms.
R7 can have the meanings that are described in EP 138 504 B1 for the 7xcex1-side chain of the steroid, with the restriction of the above-indicated disclaimer.
As R3, the 7xcex1-substituted estratrienes according to the invention preferably have a hydrogen atom. The hydroxy group, however, can also be etherified with a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 8 carbon atoms, such as, e.g., a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl or octyl radical or esterified with an acyl radical R3xe2x80x2xe2x80x94C(O)xe2x80x94, in which R3xe2x80x2 is a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms or a phenyl radical.
A fluorine atom is preferred for substituents R11.
A hydrogen atom or a radical of partial formula R17xe2x80x2xe2x80x94C(O)xe2x80x94 can stand for substituents R17, in which R17xe2x80x2 is a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms. A hydrogen atom is preferred for R17. The hydrocarbon radical can have the meaning of, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl or octyl radical.
In the compounds of general formula I according to the invention, A stands for a direct bond, a phenylene or benzylidene radical, whereby in the last case, the methylene group is bonded to carbon atom 7 of the steroid skeleton.
An aryl radical within the terms of this invention is preferably a phenyl radical, 1- or 2-naphthyl radical; the phenyl radical is preferred. Unless expressly indicated otherwise, aryl also always includes a heteroaryl radical. Examples of a heteroaryl radical are the 2-, 3- or 4-pyridinyl radical, the 2-or 3-furyl radical, the 2- or 3-thienyl radical, the 2- or 3-pyrrolyl radical, the 2-, 4- or 5-imidazolyl radical, the pyrazinyl radical, the 2-, 4- or 5-pyrimidinyl radical or 3- or 4-pyridazinyl radical.
In the ring, aralkyl groups in R20 and R31 can contain up to 14 C atoms, preferably 6 to 10 C atoms, and in the alkyl chain, they can contain 1 to 8, preferably 1 to 4 C atoms. As aralkyl radicals, for example, benzyl, phenylethyl, phenylpropyl, naphthylmethyl, and naphthylethyl are suitable.
As heteroalkylalkyl radicals, for example, furylmethyl, thienylethyl, and pyridylpropyl can be mentioned.
The aralkyl or heteroarylalkyl radical can be substituted.
If R20 and R21 with the nitrogen atom, to which they are bonded, a saturated or unsaturated heterocycle with 5 or 6 chain links, which optionally contains one or two additional heteroatoms that are selected from nitrogen, oxygen and sulfur, this is especially a pyrrolidine, piperidine, morpholine or piperazine ring.
As substituents for the aryl, heteroaryl, aralkyl and heteroarylalkyl radicals, for example, a trifluoromethyl-, pentafluoroethyl-, trifluoromethylthio-, methoxy-, ethoxy-, nitro-, cyano-, halogen- (fluorine, chlorine, bromine, iodine), hydroxy-, amino-, mono(C1-8 alkyl)- or di(C1-8 alkyl)amino, whereby both alkyl groups are identical or different, di(aralkyl)amino, whereby both aralkyl groups are identical or different (for aralkyl, see above at R20 and R31) or the 1-methoxyacetylamino radical can be mentioned.
The sulfur atom in the side chain can be present as a single sulfur bridge (sulfide), as sulfone or sulfoxide.
According to this invention, for example, the following radicals can stand for side chain R7 (A means a direct bond):
a radical of formula xe2x80x94(CH2)5xe2x80x94Zxe2x80x94R20,
xe2x80x83whereby
s is an integer from 3 to 8,
Z stands for xe2x80x94NR21 and R21 stands for a C1-C3 alkyl group,
xe2x80x83in which R20 means
a hydrogen atom,
a C1-C9 alkyl group, or
one of the groupings
xe2x80x94(CH2)mxe2x80x94CnF2n+1, whereby m and n, independently of one another, in each case is an integer from 1 to 8,
xe2x80x94(CH2)oxe2x80x94CHxe2x95x90CFxe2x80x94CpF2p+1, whereby o is 1, 2 or 3 and p is an integer from 2 to 7,
xe2x80x94(CH2)mxe2x80x94Oxe2x80x94(CH2)q-aryl, whereby m has the already indicated meaning, q is 0, 1, 2 or 3 and aryl stands for a phenyl or heteroaryl radical that is optionally substituted in one or two places,
xe2x80x94(CH2)mxe2x80x94Oxe2x80x94(CH2)rxe2x80x94CnF2n+1, whereby m and n have the already indicated meanings and r stands for an integer from 1 to 5;
a radical of formula xe2x80x94(CH2)sxe2x80x94Zxe2x80x94R20,
xe2x80x83whereby
s is an integer from 3 to 8,
Z stands for xe2x80x94NR21 and R21 stands for a C1-C3 alkyl group,
xe2x80x83in which R20 and R21 
with the nitrogen atom, to which they are bonded, form a saturated or unsaturated heterocycle with 5 or 6 chain links, which optionally contains one or two additional heteroatoms, selected from nitrogen, oxygen and sulfur, and optionally is substituted;
a radical of formula xe2x80x94(CH2)sxe2x80x94Zxe2x80x94R20,
xe2x80x83whereby
s is an integer from 3 to 8,
Z stands for xe2x80x94SOxxe2x80x94 and x stands for 0, 1 or 2,
xe2x80x83whereby R20 means
xe2x80x94(CH2)mxe2x80x94Oxe2x80x94(CH2)rxe2x80x94CnF2n+1, whereby m and n have the already indicated meanings and r stands for an integer from 1 to 5.
As specific side chains,
xe2x80x94(CH2)5N(CH3)(CH2)3C2F5 
xe2x80x94(CH2)5N(CH3)(CH2)6C2F5 
xe2x80x94(CH2)5N(CH3)(CH2)7C2F5 
xe2x80x94(CH2)5N(CH3)(CH2)8C2F5 
xe2x80x94(CH2)6N(CH3)(CH2)6C2F5 
xe2x80x94(CH2)6N(CH3)(CH2)7C2F5 
xe2x80x94(CH2)6N(CH3)(CH2)8C2F5 
xe2x80x94(CH2)5N(CH3)(CH2)2C4F9 
xe2x80x94(CH2)5N(CH3)(CH2)3C6F13 
xe2x80x94(CH2)5N(CH3)(CH2)3C8F17 
xe2x80x94(CH2)5N(CH3)(CH2)6C4F9 
xe2x80x94(CH2)5N(CH3)(CH2)6C6F13 
xe2x80x94(CH2)5N(CH3)(CH2)6C8F17 
xe2x80x94(CH2)5N(CH3)H
xe2x80x94(CH2)5N(CH3)(CH2)9H
xe2x80x94(CH2)5N(CH3)CH2CHxe2x95x90CFxe2x80x94C2F5 
xe2x80x94(CH2)5N(CH3)CH2CHxe2x95x90CFxe2x80x94C3F17 
xe2x80x94(CH2)5N(CH3)CH2CHxe2x95x90CFxe2x80x94C5F11 
xe2x80x94(CH2)5N(CH3)CH2CHxe2x95x90CFxe2x80x94C7F15 
xe2x80x94(CH2)5-1-Pyrrolidinyl
xe2x80x94(CH2)5N(CH3)(CH2)3OPhenyl
xe2x80x94(CH2)5N(CH3)(CH2)3OBenzyl
xe2x80x94(CH2)5N(CH3)(CH2)3O(CH2)3C2F5 
xe2x80x94(CH2)9S(CH2)3C2F5 
xe2x80x94(CH2)9SO(CH2)3C2F5 
xe2x80x94(CH2)9SO2(CH2)3C2F5 
can be mentioned.
Specific compounds of general formula I are described in the examples.
In addition to these compounds of general formula 1, if a nitrogen atom is contained in R7, this invention also relates to their physiologically compatible addition salts with organic and inorganic acids, pharmaceutical preparations that contain these compounds of general formula I inclusive of the addition salts as well as their use for the production of pharmaceutical agents.
Inorganic and organic acids, as are known to one skilled in the art for the formation of physiologically compatible salts, are suitable for the formation of acid addition salts. As addition salts with acids, especially hydrochlorides, hydrobromides, acetates, citrates, oxalates, tartrates and methanesulfonates can be cited.
The compounds of general formula I represent compounds with strong antiestrogenic action.
The compounds according to the invention are either pure antiestrogens or so-called partial antagonists, i.e., antiestrogens with partial estrogenic action such as tamoxifen or raloxifen. In contrast to the tamoxifen, their agonistic, estrogenic action is expressed in a tissue-selective manner in the case of partial antagonists of general formula I. In particular, the agonistic action occurs in bone, in the cardiovascular system and in the central nervous system. In particular, no action or only slightly agonistic action occurs in the uterus.
Compounds with antiestrogenic properties, i.e., substances with inhibiting actions compared to estrogens have already been described extensively.
As the compounds that come closest structurally to these compounds of general formula I, the steroid derivatives that are known from EP 0 138 504 B1 can be considered. The 7xcex1-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-n-nonyl]-estra-1,3,5(10)-triene-3,17xcex2-diol (EP-A 0 138 504, page 58, penultimate compound) is currently under clinical development for hormone-dependent tumors (breast cancer) and represents the compound that is best known at this time, i.e., the one with the strongest antiestrogenic activity, of these steroid derivatives.
Pharmaceutical compositions, which contain sex steroid inhibitors, which have a steroidal skeleton that has a 7xcex1-side chain in the case of the simultaneous presence of at least one other substituent in 14-, 15- or 16-position, are the subject of EP-A 0 376 576.
A considerable number of the most widely varied compoundsxe2x80x94i.a. those of steroidal origin and those with a 2-phenylindole skeletonxe2x80x94which act as antiestrogens and/or suppress the estrogen biosynthesis, are disclosed in WO 93/10741.
Other steroidal antiestrogens, which carry an 11xcex2-phenyl radical, are described in EP-AS 0 384 842 and 0 629 635.
Compounds according to the invention are antiestrogens with mostly stronger antiestrogenic action than the already mentioned 7xcex1-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-n-nonyl]-estra-1,3,5(10)-triene-3,17xcex2-diol and/or compounds that are distinguished from 7xcex1-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-n-nonyl]-estra-1,3,5(10)-triene-3,17xcex2-diol by their partial estrogenic action.
The compounds of general formula I according to this application are distinguished by the additional 11xcex2-fluorine atom in comparison to the already known steroid derivatives according to EP-A 0 138 504 and EP-A 0 367 576.
This structural modification is of decisive importance for the advantageous properties of the compounds according to the invention.
The antiestrogenic action of the compounds according to the invention was determined in transactivation assays [Demirpence, E.; Duchesne, M.-J.; Badia, E.; Gagne, D. and Pons, M.: MVLN Cells: a Bioluminescent MCF-7-Derived cell Line to Study the Modulation of Estrogenic Activity; J. Steroid. Molec. Biol. Vol. 46, No. 3, 355-364 (1993) and Berry, M.; Metzger, D.; Chambon, P.: Role of the Two Activating Domains of the Estrogen Receptor in the Cell-type and Promoter-context Dependent Agonistic Activity of the Anti-estrogen 4-Hydroxytamoxifen; The EMBO Journal Vol. 9, 2811-2818 (1990)].
The MVLN cells are transfixed in a stable manner with reporter gene Vit-TK-LUC. The antiestrogenic active strength was determined in the presence of 0.1 nM of estradiol.
The IC50 values for the new compounds are in the nanomolar range. In the MVLN cell line, the following IC50 values are produced for the compound of Examples 3 and 8 (execution of test according to the above-indicated bibliographic references):
The uterus growth test in infantile rats, p.o. (test on antiestrogenic action in vivo) also confirms the antiestrogenic action of the compounds according to the invention. The test was performed as described below:
Principle of the Method
In rodents, the uterus reacts to the application of estrogens with an increase in weight (both proliferation and water retention). This growth can be inhibited in a dose-dependent manner by simultaneous administration of compounds that have an antiestrogenic action.
Animals:
Infantile female rats weighing 35-45 g at the beginning of the test, 5-6 animals per dose.
Formulation and Administration of the Substances:
For the p.o. administration, the substances are dissolved in 1 part ethanol (E) and made up with 9 parts peanut oil (Exc3x96).
Test Batch
The young rats just dropped by the mothers are delivered for acclimation one day before the beginning of treatment and immediately supplied with foodxe2x80x94right in the cage. The treatment is then carried out once daily over 3 days in combination with 0.5 xcexcg of estradiol benzoate (EB). EB is always administered subcutaneously (s.c.), while the test substance is administered p.o. (perorally). 24 hours after the last administration, the animals are weighed, killed and the uteri are removed. The moist weight (less contents) is determined from the prepared uteri.
Controls
Negative control: Vehicle (E/Exc3x96), 0.2 ml/animal/day
Positive control: 0.5 xcexcg of EB/0.1 ml/animal/day
Evaluation
The average values are determined with standard deviation (X+SD) and the significance of the differences in the control group (EB) in the Dunnett Test (p less than 0.05) for each group from the relative organ weights (mg/100 g of body weight). The calculation of the inhibition (in %) compared to the EB-control is carried out with a program. The relative actions of the test substances are determined by co-variance analysis and regression analysis.
As pure antiestrogens for the purposes of this invention, those compounds of general formula I that show no action or, in the best case, only slightly agonistic action, i.e., an agonistic action up to about 20% of the action of estradiol, in the in-vitro test on estrogenic action that is described below can be considered.
The transition between the pure antiestrogens and the partial agonists, the tissue-selective estrogens, is seamless. Compounds that have a slightly agonistic action can also be used in the indications that are mentioned below for pure antiestrogens.
The partial estrogenic action of compounds according to the invention was determined by transactivation assays. HeLa cells were transfixed with human estrogen receptor expression vector (HEGO) and a reporter gene rPR-TK-CAT. This reporter gene contains the xe2x80x9cEstrogen Responsive Elementxe2x80x9d of the rabbit progesterone receptor gene (+698/+729 region) before a TK-CAT gene (Savouret, J. F.; Bailly, A.; Misrahi, M.; Rauch, C.; Redeuilh, G.; Chauchereau, A.; Milgrom, E., Characterization of the Hormone Responsive Element Involved in the Regulation of the Progesterone Receptor Gene. EMBO J. 10, 1875-1883 (1991).
The estrogenic action was determined at a concentration of 1 xcexcm.
The compounds according to the invention, especially if they are pure antiestrogens, are suitable for treatment of estrogen-dependent diseases, for example breast cancer (second-line treatement of tamoxifen-resistant breast cancer; for adjuvant treatment of breast cancer instead of tamoxifen), endometrial cancer, prostate cancer, prostatic hyperplasia, anovulatory infertility and elanoma.
In addition, the pure antiestrogens of general formula I can be used as components in the products that are described in EP 346 014 B1 which contain an estrogen and a pure antiestrogen, specifically for simultaneous, sequential or separate use for selective estrogen therapy of peri- or postmenopausal women. The compounds of general formula I, especially if these are pure antiestrogens, can be used together with antigestagens (competitive progesterone antagonists) for the treatment of hormone-dependent tumors (EP 310 542 A).
Other indications in which the compounds of the general formula can be used are male hair loss, diffuse alopecia, alopecia that is caused by chemotherapy as well as hirsutism (Hye-Sun Oh and Robert C. Smart, Proc. Natl. Acad. Sci. USA, 93 (1996) 12525-12530).
In addition, the compounds of general formula I can be used for the production of medications for treating endometriosis and endometrial carcinomas.
The compounds of general formula I can also be used for the production of pharmaceutical compositions for male and female birth control (male birth control: DE-A 195 10 862.0).
The compounds of general formula I with tissue-selective partial estrogenic action can be used primarily for prophylaxis and treatment of osteoporosis and for the production of preparations for substitution therapy in pre-, peri- and post-menopause (HRT=hormone replacement therapy) (Black, L. J.; Sato, M.; Rowley, E. R.; Magee, D. E.; Bekele, A.; Williams, D. C.; Cullinan, G. J.; Bendele, R.; Kauffman, R. F.; Bensch, W. R.; Frolik, C. A.; Termine, J. D. and Bryant, H. U.: Raloxifene [Lyophilizate 139481 HCl] Prevents Bone Loss and Reduces Serum Cholesterol without Causing Uterine Hypertrophy in Ovariectomized Rats; J. Clin. Invest. 93: 63-69, 1994).
The invention also relates to pharmaceutical preparations that contain at least one compound of general formula I (or physiologically compatible addition salts with organic and inorganic acids of them) and the use of these compounds for the production of pharmaceutical agents, especially for treating estrogen-dependent diseases and tumors and pharmaceutical agents for hormone replacement therapy (HRT).
The compounds according to the invention and the acid addition salts are suitable for the production of pharmaceutical compositions and preparations. As active ingredients, the pharmaceutical compositions or pharmaceutical agents contain one or more of the compounds according to the invention or their acid addition salts, optionally mixed with other pharmacologically or pharmaceutically active substances. The production of the pharmaceutical agents is carried out in a known way, whereby the known and commonly used pharmaceutical adjuvants and other commonly used vehicles and diluents can be used.
As such vehicles and adjuvants, for example, those are suitable that are recommended or indicated in the following bibliographic references as adjuvants for pharmaceutics, cosmetics and related fields: Ullmans Encyklopxc3xa4die der technischen Chemie [Ullman""s Encyclopedia of Technical Chemistry], Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), pages 918 and ff.; issued by Czetsch-Lindenwald, Hilfsstoffe fxc3xcr Pharmazie und angrenzende Gebiete [Adjuvants for Pharmaceutics and Related Fields]; Pharm. Ind. Issue 2, 1961, pages 72 and ff.; Dr. H. P. Fiedler, Lexikon der Hilfsstoffe fxc3xcr Pharmazie, Kosmetik und angrenzende Gebiete [Dictionary of Adjuvants for Pharmaceutics, Cosmetics and Related Fields] Cantor K G, Aulendorf in Wxc3xcrttemberg 1971.
The compounds can be administered orally or parenterally, for example intraperitoneally, intramuscularly, subcutaneously or percutaneously. The compounds can also be implanted in the tissue. The amount of the compounds to be administered varies within a wide range and can cover any effective amount. Based on the condition to be treated and the type of administration, the amount of administered compound can be 0.1-25 mg/kg of body weight, preferably 0.5-5 mg/kg of body weight, per day. In humans, this corresponds to a daily dose of 5 to 1250 mg. The preferred daily dosage in humans is 50 to 200 mg. This is true especially for tumor therapy.
For oral administration, capsules, pills, tablets, coated tablets, etc., are suitable. In addition to the active ingredient, the dosage units can contain a physiologically compatible vehicle, such as, for example, starch, sugar, sorbitol, gelatin, lubricant, silicic acid, talc, etc. The individual dosage units for oral administration can contain, for example, 5 to 500 mg of active ingredient.
To achieve better bio-availability of the active ingredient, the compounds can also be formulated as cyclodextrin clathrates. For this purpose, the compounds are reacted with xcex1-, xcex2- or xcex3-cyclodextrin or derivatives thereof (PCT/EP95/02656).
For parenteral administration, the active ingredients can be dissolved or suspended in a physiologically compatible diluent. As diluent, very frequently oils with or without the addition of a solubilizer, a surfactant, a suspending agent or emulsifier are used. Examples of oils that are used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.
The compounds of general formula I can also be formulated in the form of a solution that is determined for oral administration and that in addition to the active compound of general formula I contains
a) a pharmaceutically compatible oil and/or
b) a pharmaceutically compatible lipophilic surfactant and/or
c) a pharmaceutically compatible hydrophilic surfactant and/or
d) a pharmaceutically compatible water-miscible solvent.
In this respect, reference is made in addition to WO 97/21440.
The compounds can also be used in the form of a depot injection or an implant preparation, which can be formulated in such a way that a delayed release of active ingredient is made possible.
As inert materials, implants can also contain, for example, biodegradable polymers or synthetic silicones such as, for example, silicone gum. In addition, the active ingredients can be embedded in, for example, a patch for percutaneous administration.
For the production of intravaginal systems (e.g., vaginal rings) or intrauterine systems (e.g., pessaries, spirals) that are loaded with active compounds of general formula I, various polymers such as, for example, silicone polymers, ethylene vinyl acetate, polyethylene or polypropylene are suitable.
The compounds according to the invention can be produced as described below. The examples below are used for a more detailed explanation of the invention. Other compounds of general formula I can be obtained by an analogous procedure using analogous reagents in the data contained in the examples.
As processes to create side chain R7 in the compounds according to the invention, especially also the methods of side-chain introduction and side-chain build-up that are described in EP 0 138 504 B1 are suitable, whereby then as a starting compound, instead of xcex946-nortestosterone, its 17-hydroxy group is acylated, and the 11xcex2-fluorine compound 11xcex2-fluorine-xcex946-androstenedione can be used. The reduction of the 17-keto group then takes place in a later stage.
The compounds of general formula I, in which R31 is a radical of formula xe2x80x94C(O)R33, can be converted by complete reduction of the keto group of the carboxylic acid amide with lithium aluminum hydride or similar reducing agents according to the method that is familiar to one skilled in the art into the compounds in which R31 is then xe2x80x94CH2xe2x80x94R33.
A thio bridge in the side chain can be oxidized with sodium periodate into sulfoxide (Example 24n)); the sulfones are obtained from the sulfides with a peracid as an oxidizing agent, e.g., m-chloroperbenzoic acid.
The saponification of the ester groupings as well as esterification and etherification of free hydroxy groups is carried out in each case according to established processes of organic chemistry. By observing the various reactivity of the esterified and free 3- and 17-hydroxy group, the 3,17-diester can be cleaved selectively in 3-position, and the 3-hydroxy-17-acyloxy compound can then be additionally functionalized specifically in the 3-position; it is equally possible to esterify or to etherify the 3,17-dihydroxy compound selectively only in the 3-position and then to introduce specifically another radical into the 17-position as already in the 3-position.
The acid addition salts of the compounds of general formula I can also be produced from the compounds of general formula I according to standard processes.
The examples below are used for a more detailed explanation of the invention: